Implantable medical devices are implanted into the body for various reasons, including orthopedics (e.g., hip replacement, spinal procedures, knee replacement, bone fracture repair, etc. In view of the structural integrity requirements of such devices, materials of fabrication are limited, and conventionally include metal, plastic and composites.
The benefits derived from these devices are often offset by infection, which can lead to sepsis and death. The most common organisms causing infections are Staphylococcus epidermidis and Staphylococcus aureus. Other gram-positive bacteria, gram-negative bacteria and fungal organisms also are problematic. Of particular concern is Methicillin-resistant Staphylococcus aureus (MRSA), a type of staphylococcus bacteria that are resistant to many antibiotics. As a result, MRSA infections are more difficult to treat than ordinary staph infections, and have become a serious problem.
Many pathogenic bacteria can form multicellular coatings, called biofilms on bioengineered implants. Biofilms can facilitate the proliferation and transmission of microorganisms by providing a stable protective environment. These biofilms, when well developed, can disseminate bacterial planktonic showers which can result in broad systemic infection.
Bioengineered materials act as excellent hosts for the formation of bacterial biofilms. Occasionally, (the implant itself carries the infecting organism) implants develop very tenacious biofilms seeded by infecting organisms. When this occurs, usually the implant must be removed, the patient must be treated with a prolonged course of one or more antibiotics in an effort to cure the infection, and a new implant is then re-implanted. This obviously subjects the patient to additional trauma and pain, and is extremely expensive.
Accordingly, much research has been devoted toward preventing colonization of bacterial and fungal organisms on the surfaces of orthopedic implants by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. For example, silver is a powerful, natural antibiotic and preventative against infections. Acting as a catalyst, it disables the enzyme that one-cell bacteria, viruses and fungi need for their oxygen metabolism. They suffocate without corresponding harm occurring to human enzymes or parts of the human body chemistry. The result is the destruction of disease-causing organisms in the body. Silver disrupts bacteria membranes, inter-membrane enzymes, and DNA transcription.
Ceramics such as zeolite function as a cation cage, being able to be loaded with silver and other cations having antimicrobial properties. Metal zeolites can be used as an antimicrobial agent, such as by being mixed with the resins used as thermoplastic materials to make the implantable devices, or as coatings to be applied to the devices; see, for example, U.S. Pat. No. 6,582,715, the disclosure of which is hereby incorporated by reference. The antimicrobial metal zeolites can be prepared by replacing all or part of the ion-exchangeable ions in zeolite with ammonium ions and antimicrobial metal ions. Preferably, not all of the ion-exchangeable ions are replaced.
One particular thermoplastic resin that has been found to be useful in an implant is polyetheretherketone (PEEK). PEEK is suitable because its modulus closely matches that of bone. It is possible, under conditions of high temperature and high shear, to incorporate antimicrobial zeolite, such as silver zeolite, into PEEK, such as by mixing doped metal zeolites into molten PEEK (melting point between 300 and 400° C.), followed by molding and processing of the composite blend. Pure PEEK is very light tan and silver zeolite is white. However, the heated melt after processing becomes a dark brown color. The reasons for color development may include oxidation of some of the silver to silver oxides, which may be less soluble and less effective than pure silver cation attached to the zeolite cage. Silver metal can have catalytic properties and may cause breakdown and partial decomposition of the PEEK polymer. Grades of PEEK approved for implantation are very pure and inert and need to pass stringent cytotoxicity testing before being allowed to be implanted into mammals.
The ISO 10993 set entails a series of standards for evaluating the biocompatibility of a medical device prior to a clinical study. These documents were preceded by the Tripartite agreement and are a part of the harmonization of the safe use evaluation of medical devices. Those standards include:                ISO 10993-1:2003 Biological evaluation of medical devices Part 1: Evaluation and testing        ISO 10993-2:2006 Biological evaluation of medical devices Part 2: Animal welfare requirements        ISO 10993-3:2003 Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity        ISO 10993-4:2002/Amd 1:2006 Biological evaluation of medical devices Part 4: Selection of tests for interactions with blood        ISO 10993-5:2009 Biological evaluation of medical devices Part 5: Tests for in vitro cytotoxicity        ISO 10993-6:2007 Biological evaluation of medical devices Part 6: Tests for local effects after implantation        ISO 10993-7:1995 Biological evaluation of medical devices Part 7: Ethylene oxide sterilization residuals        ISO 10993-8:2001 Biological evaluation of medical devices Part 8: Selection of reference materials        ISO 10993-9:1999 Biological evaluation of medical devices Part 9: Framework for identification and quantification of potential degradation products        ISO 10993-10:2002/Amd 1:2006 Biological evaluation of medical devices Part 10: Tests for irritation and delayed-type hypersensitivity        ISO 10993-11:2006 Biological evaluation of medical devices Part 11: Tests for systemic toxicity        ISO 10993-12:2007 Biological evaluation of medical devices Part 12: Sample preparation and reference materials (available in English only)        ISO 10993-13:1998 Biological evaluation of medical devices Part 13: Identification and quantification of degradation products from polymeric medical devices        ISO 10993-14:2001 Biological evaluation of medical devices Part 14: Identification and quantification of degradation products from ceramics        ISO 10993-15:2000 Biological evaluation of medical devices Part 15: Identification and quantification of degradation products from metals and alloys        ISO 10993-16:1997 Biological evaluation of medical devices Part 16: Toxicokinetic study design for degradation products and leachables        ISO 10993-17:2002 Biological evaluation of medical devices Part 17: Establishment of allowable limits for leachable substances        ISO 10993-18:2005 Biological evaluation of medical devices Part 18: Chemical characterization of materials        ISO/TS 10993-19:2006 Biological evaluation of medical devices Part 19: Physio-chemical, morphological and topographical characterization of materials        ISO/TS 10993-20:2006 Biological evaluation of medical devices Part 20: Principles and methods for immunotoxicology testing of medical devices        
There is a possibility that reactions catalyzed by silver while silver zeolite is being incorporated into PEEK, at high temperature, could generate toxic materials which could cause the product to fail these tests. Further still, at these high processing temperatures, metal zeolite can release moisture if it is not extremely dry. This moisture can cause the formation of voids in the polymer melt and can contribute to the decomposition of the PEEK polymer and to oxidation of metals, such as silver, copper and/or zinc, incorporated into the zeolite antimicrobial. Although the presence of voids may not be critical for certain non-load bearing applications, the absence of voids is critical for load-bearing applications such as spinal repair.
If the process of incorporating metal zeolites is carried out in air, severe oxidation can occur as the temperature is raised, and moisture and oxygen come into contact with the metal ions. Silver will rapidly darken to a dark brown or black color. Also, the incorporation of significant quantities of metal zeolites into the PEEK polymer can affect the viscosity and rheology of the composition.
Accordingly, it would be desirable to provide medical devices with effective antimicrobial activity in order to reduce the growth of bacteria and risk of infection that do not suffer from the aforementioned drawbacks.